Neuroscience
Rett syndrome and neurodevelopmental disorders
Since the beginning of her research activity, NL main interests were in chromatin structure and epigenetics and their influence on gene expression. Thereby, in the last period of her Post-Doc activity in dr. Wolffe’s lab (NIH/USA), she got interested on DNA methylation and MeCP2. At that time the protein was very little characterized and was still not recognized as the main cause of Rett syndrome. The interest on MeCP2 was reinforced by the discovery in 1999 of its association with Rett syndrome and other neurological disorders. Since then, she focused the lab research on a better characterization of the methyl binding protein, studying its partners, its phosphorylation and the molecular consequences of its deficiency. In the last years, she moved her research forward, including preclinical studies. These studies have brought to 26 original papers, 3 invited reviews, 1 commentary and 1 chapter of book edited by Elsevier.
Eventually, because of the interest in MeCP2 phosphorylation, she initiated a study aimed at identifying the involved kinases. Obtained results led NL to focus part of her studies on CDKL5, an X-linked gene responsible of a severe neurodevelopmental disorder mainly affecting females and partly resembling to a variant form of Rett syndrome. Obtained results have led to 19 papers on CDKL5, that overall have largely contributed to the current knowledge of CDKL5 activity and regulation.
Scopus Res. ID:6603941648
ORCID ID: https://orcid.org/0000-0003-0820-3155
Research activity
General research
Our research activity focuses on neurodevelopmental diseases, with a particular attention to those caused by mutations in MECP2. To date, there is no cure for these diseases and patients are mainly treated with drugs for core symptoms. This is partly due to an insufficient knowledge of the pathogenic mechanisms, as well as to a complexity of the altered biological processes. Our research aims at identifying the molecular and cellular defects underlying these diseases, and in particular Rett syndrome (RTT), in order to identify new therapeutic targets and biomarkers useful for studying the progression of the disease. Further, we are testing innovative molecular and cellular approaches for the treatment of RTT. Our research mainly uses transgenic mouse models mutated in Mecp2 (or Cdkl5), and primary cultured neurons. Obtained results are validated in mutated human cells.
Current main projects
Identification and characterization of new modifier genes of Rett syndrome
Mutations in MECP2 cause deregulation of a large number of genes. Alterations of some of these could contribute to typical neurobiological defects of RTT; their identification could lead to a better comprehension of the disease and/or the identification of new therapeutic targets.
We have recently distinguished some genes consistently altered both in cellular and animal models of RTT, and in patients. According to their functions, we have initiated projects aiming at characterizing, through approaches of molecular and cellular biology, their involvement in experimental models of the disease, as well as in physiological conditions, if the information available is limited.
New therapeutic approaches for Rett syndrome
Based on our recent publications or literature evidence, we are evaluating the effectiveness of new molecular and pharmacological approaches for the treatment of Rett syndrome. Amelioration of typical molecular and behavioral phenotypes is tested in mouse models of Mecp2 and in cells derived from RTT patients.
Characterization of the molecular mechanisms responsible for the benefits exerted by staminal cell transplantation In Rett syndrome
We have recently found that NPC transplantation in the Mecp2 KO mouse brain significantly slows down the progression of symptoms, alleviating its severity. Through multiple cellular and molecular biology approaches, we aim at isolating the molecular mechanisms activated by transplanted cells, which could reveal new therapeutic approaches.
Gandaglia A, Brivio E, Carli S, Palmieri M, Bedogni F, Stefanelli G, Bergo A, Leva B, Cattaneo C, Pizzamiglio L, Cicerone M, Bianchi V, Kilstrup- Nielsen C, D'Annessa I, Di Marino D, D'Adamo P, Antonucci F, Frasca A, Landsberger N. A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome. Mol Neurobiol. 2018 Nov 6.
D'Annessa I, Gandaglia A, Brivio E, Stefanelli G, Frasca A, Landsberger N, Di Marino D. Tyr120Asp mutation alters domain exibility and dynamics of MeCP2 DNA binding domain leading to impaired DNA interaction: Atomistic characterization of a Rett syndrome causing mutation. Biochim Biophys Acta Gen Subj. 2018 May;1862(5):1180-1189.
Cobolli Gigli C, Scaramuzza L, De Simone M, Rossi RL, Pozzi D, Pagani M, Landsberger N, Bedogni F. Lack of Methyl-CpG Binding Protein 2 (MeCP2) Affects Cell Fate Refinement During Embryonic Cortical Development. Cereb Cortex. 2018 Jan 17.
Good KV, Martínez de Paz A, Tyagi M, Cheema MS, Thambirajah AA, Gretzinger TL, Stefanelli G, Chow RL, Krupke O, Hendzel M, Missiaen K, Underhill A, Landsberger N, Ausió J. Trichostatin A decreases the levels of MeCP2 expression and phosphorylation and increases its chromatin binding affinity. Epigenetics. 2017;12(11):934-944.
Stefanelli G, Gandaglia A, Costa M, Cheema MS, Di Marino D, Barbiero I, Kilstrup-Nielsen C, Ausió J, Landsberger N. Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association. Sci Rep. 2016; 6:28295.
Bedogni F, Cobolli Gigli C, Pozzi D, Rossi RL, Scaramuzza L, Rossetti G, Pagani M, Kilstrup- Nielsen C, Matteoli M, Landsberger N. Defects during Mecp2 null embryonic cortex development precede the onset of overt neurological symptoms. Cereb Cortex. 2016 Jun;26(6):2517-2529.
Conti V, Gandaglia A, Galli F, Tirone M, Bellini E, Campana L, Kilstrup-Nielsen C, Rovere- Querini P, Brunelli S, Landsberger N. MeCP2 affects skeletal muscle growth and morphology through non cell-autonomous mechanisms. PLoS One. 2015 Jun 22;10(6):e0130183.
La Montanara P, Rusconi L, Locarno A, Forti L, Barbiero I, Tramarin M, Chandola C, Kilstrup- Nielsen C, Landsberger N. Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5. J Biol Chem. 2015 Feb 13;290(7):4512-27.
Bergo A, Strollo M, Gai M, Barbiero I, Stefanelli G, Sertic S, Cobolli Gigli C, Di Cunto F, Kilstrup-Nielsen C, Landsberger N. Methyl-CpG binding protein 2 (MeCP2) localizes at the centrosome and is required for proper mitotic spindle organization. J Biol Chem. 2015 Feb 6;290(6):3223-37.
Rusconi F, Paganini L, Braida D, Ponzoni L, Toffolo E, Maroli A, Landsberger N, Bedogni F, Turco E, Pattini L, Altruda F, De Biasi S, Sala M, Battaglioli E. LSD1 neurospecific alternative splicing controls neuronal excitability in mouse models of epilepsy. Cereb Cortex. 2015 Sep;25(9):2729-40.
Bellini E, Pavesi G, Barbiero I, Bergo A, Chandola C, Nawaz MS, Rusconi L, Stefanelli G, Strollo M, Valente MM, Kilstrup-Nielsen C, Landsberger N. MeCP2 post-translational modifications: a mechanism to control its involvement in synaptic plasticity and homeostasis? Front Cell Neurosci. 2014 Aug 13;8:236.
Bedogni F, Rossi RL, Galli F, Cobolli Gigli C, Gandaglia A, Kilstrup-Nielsen C, Landsberger N. Rett syndrome and the urge of novel approaches to study MeCP2 functions and mechanisms of action. Neurosci Biobehav Rev. Pt 2014 Oct;46 Pt 2:187-201.